Abstract
BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes. METHODS: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed ≥1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed. RESULTS: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with ≥2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with ≥2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of β-cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with ≥2 autoantibodies (p<0.0001). CONCLUSION: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity.